Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study.

INTRODUCTION: Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR). METHODS: Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling. RESULTS: Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects. CONCLUSION: Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

Uptake of a Consumer-Focused mHealth Application for the Assessment and Prevention of Heart Disease: The <30 Days Study.

BACKGROUND: Lifestyle behavior modification can reduce the risk of cardiovascular disease, one of the leading causes of death worldwide, by up to 80%. We hypothesized that a dynamic risk assessment and behavior change tool delivered as a mobile app, hosted by a reputable nonprofit organization, would promote uptake among community members. We also predicted that the uptake would be influenced by incentives offered for downloading the mobile app. OBJECTIVE: The primary objective of our study was to evaluate the engagement levels of participants using the novel risk management app. The secondary aim was to assess the effect of incentives on the overall uptake and usage behaviors. METHODS: We publicly launched the app through the iTunes App Store and collected usage data over 5 months. Aggregate information included population-level data on download rates, use, risk factors, and user demographics. We used descriptive statistics to identify usage patterns, t tests, and analysis of variance to compare group means. Correlation and regression analyses determined the relationship between usage and demographic variables. RESULTS: We captured detailed mobile usage data from 69,952 users over a 5-month period, of whom 23,727 (33.92%) were registered during a 1-month AIR MILES promotion. Of those who completed the risk assessment, 73.92% (42,380/57,330) were female, and 59.38% (34,042/57,330) were <30 years old. While the older demographic had significantly lower uptake than the younger demographic, with only 8.97% of users aged ≥51 years old downloading the app, the older demographic completed more challenges than their younger counterparts (F8, 52,422 = 55.10, P<.001). In terms of engagement levels, 84.94% (44,537/52,431) of users completed 1-14 challenges over a 30-day period, and 10.03% (5,259/52,431) of users completed >22 challenges. On average, users in the incentives group completed slightly more challenges during the first 30 days of the intervention (mean 7.9, SD 0.13) than those in the nonincentives group (mean 6.1, SD 0.06, t28870=-12.293, P<.001, d=0.12, 95% CI -2.02 to -1.47). The regression analysis suggested that sex, age group, ethnicity, having 5 of the risk factors (all but alcohol), incentives, and the number of family histories were predictors of the number of challenges completed by a user (F14, 56,538 = 86.644, P<.001, adjusted R(2) = .021). CONCLUSION: While the younger population downloaded the app the most, the older population demonstrated greater sustained engagement. Behavior change apps have the potential to reach a targeted population previously thought to be uninterested in or unable to use mobile apps. The development of such apps should assume that older adults will in fact engage if the behavior change elements are suitably designed, integrated into daily routines, and tailored. Incentives may be the stepping-stone that is needed to guide the general population toward preventative tools and promote sustained behavior change.

Engaging Patients in Online Self-Care Technologies for Chronic Disease Management.

A common perception is that the use of Internet-based self-care systems is best suited for a younger, tech-proficient population, and that these systems will increase the burden on patients with complex chronic conditions. The study stratified patients with diabetes into three regimens of use of an Internet-based diabetes self-care portal. Results show that patients were more likely to adhere to a diurnal regimen than a variable regimen, and older patients, over the age of 60, were more adherent than younger patients, regardless of regimen. This suggests that common misconceptions should be reconsidered when prescribing Internet-based interventions for patients with chronic illness.

After-exercise heart rate variability is attenuated in postmenopausal women and unaffected by estrogen therapy.

OBJECTIVE: Delayed heart rate (HR) recovery in the immediate postexercise period has been linked to adverse cardiovascular prognosis. The after effects of an acute bout of exercise on HR modulation in postmenopausal women (PMW) and the influence of estrogen therapy are unknown. METHODS: In 13 sedentary PMW (54 ± 2 y, mean ± SEM), we assessed HR variability (HRV)--an index of HR modulation--and the influence of estrogen therapy on HRV. HRV in the frequency domain was quantified during supine rest and again 60 minutes after treadmill exercise for 45 minutes, at 60% VO2peak. PMW were studied before and after 4 weeks of oral estradiol. To obtain reference values for the after effects of exercise on HRV in healthy young women, 14 premenopausal women (PreM) completed the identical exercise protocol. RESULTS: Compared with PreM, PMW demonstrated lower high frequency (vagal modulation) and total HRV (P < 0.05) at rest. In PreM, all HRV values were similar before and after exercise. In contrast, in PMW after exercise, despite having identical HR to PreM, high frequency and total HRV were all lower (all P ≤ 0.01) compared with pre-exercise HRV values. Estrogen therapy had no effect on pre or postexercise values for HRV. CONCLUSIONS: When compared with PreM, PMW have identical HR, but lower vagal HR modulation at rest and delayed HRV recovery after exercise. Estrogen does not restore baseline HRV or accelerate HRV recovery postexercise, suggesting aging rather than estrogen deficiency per se may lower HRV in PMW.

Evaluation of a clinical tool to test and adjust the programmed overnight basal profiles for insulin pump therapy: a pilot study.

OBJECTIVE: Clinical protocols for basal rate testing and adjustment are needed for effective insulin pump therapy. We evaluated the effects of a continuous glucose monitoring (CGM)-based semiautomated basal algorithm on glycemia. METHODS: We developed and piloted a basal rate analyzer that interpreted CGM data from overnight fasts and recommended dose changes for subsequent nights. Subjects uploaded data online using sensor-augmented pumps for evaluation by the analyzer after each of 5 overnight fasts conducted over 2 to 8 weeks. It was designed to be conservative and iterative, making changes that did not exceed 10% at each iteration. The standard deviation and interquartile range of CGM values from midnight to 7 am (SD12-7am and IQR12-7am) over 3 baseline and 3 postintervention nights, hypoglycemia incidence (CGM values <4.0 mmol/L), and glycated hemoglobin (A1C) were compared. RESULTS: Twenty subjects with mean ages of 38±13 years and A1C 7.6%±0.8% (60±8.7 mmol/mol) underwent the 5 iterations of basal assessments over 5±3 weeks. SD12-7am and IQR12-7am did not change from baseline to postintervention (1.57±0.8 to 1.63±0.8 mmol/L; p=0.35; 3.66±2.07 to 3.47±2.26 mmol/L; p=0.90). However, mean glucose values were lower between 2 to 3 am at baseline compared to postintervention; 3-night hypoglycemia incidence declined from 1.6±1.8 to 0.5±0.7 episodes (p=0.01), and A1C improved from 7.6%±0.8% to 7.4%±0.9% (60%±8.7% to 57%±9.8% mmol/mol; p=0.03). CONCLUSIONS: The use of a basal rate analyzer was associated with reduced hypoglycemia and improved A1C. However, overnight glycemic stability was not improved. Further research into the efficacy of the CGM-based semiautomated algorithm is warranted.

Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

BACKGROUND: Many patients with severe obstructive sleep apnea (OSA) do not complain of excessive daytime sleepiness (EDS), possibly due to increased sympathetic nervous activity (SNA) and accompanying heightened alertness. We hypothesized that in patients with OSA, those without subjective EDS (Epworth Sleepiness Scale, ESS score < 11) would have higher very low frequency (VLF) heart rate variability (HRV) during sleep, reflecting greater sympathetic heart rate modulation than patients with an ESS score ≥ 11. METHODS: Patients with severe OSA (AHI ≥ 30: 26 with and 65 without heart failure) were divided into those with and without EDS. Heart rate (HR) signals were acquired in stage 2 sleep during periods of recurrent apneas and hypopneas and submitted to coarse graining spectral analysis, which extracts harmonic, neurally mediated contributions to HRV from total spectral power. Because the apnea-hyperpnea cycle entrains muscle SNA at VLF (0 to 0.04 Hz), VLF power was our principal between-group comparison. RESULTS: Subjects without EDS had higher harmonic VLF power (944 ± 839 vs 447 ± 461 msec(2), p = 0.003) than those with EDS, irrespective of the presence or absence of heart failure (1218 ± 944 vs 426 ± 299 msec(2), p = 0.043, and 1029 ± 873 vs 503 ± 533 msec(2), p = 0.003, respectively). ESS scores correlated inversely with VLF power in all (r = -0.294, p = 0.005) and in heart failure subjects (r = -0.468, p = 0.016). CONCLUSIONS: Patients with severe OSA but without EDS have higher VLF-HRV than those with EDS. This finding suggests that patients with severe OSA but without EDS have greater sympathetic modulation of HRV than those with EDS that may reflect elevated adrenergically mediated alertness. CITATION: Taranto Montemurro L; Floras JS; Picton P; Kasai T; Alshaer H; Gabriel JM; Bradley TD. Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

Advancement of the artificial pancreas through the development of interoperability standards.

Despite advancements in the development of the artificial pancreas, barriers in the form of proprietary data and communication protocols of diabetes devices have made the integration of these components challenging. The Artificial Pancreas Standards and Technical Platform Project is an initiative funded by the JDRF Canadian Clinical Trial Network with the goal of developing device communication standards for the interoperability of diabetes devices. Stakeholders from academia, industry, regulatory agencies, and medical and patient communities have been engaged in advancing this effort. In this article, we describe this initiative along with the process involved in working with the standards organizations and stakeholders that are key to ensuring effective standards are developed and adopted. Discussion from a special session of the 12th Annual Diabetes Technology Meeting is also provided.

Improving diabetes management with a patient portal: a qualitative study of diabetes self-management portal.

BACKGROUND: Effective management and care of diabetes is crucial to reducing associated risks such as heart disease and kidney failure. With increasing access and use of the Internet, online chronic disease management is being explored as a means of providing patients with support and the necessary tools to monitor and manage their disease. OBJECTIVE: The objective of our study was to evaluate the experience of patients and providers using an online diabetes management portal for patients. METHODS: Participants were recruited from a large sample population of 887 for a follow-up questionnaire to be completed after 6 months of using the patient portal. Participants were presented with the option to participate in an additional interview and, if the participant agreed, a time and date was scheduled for the interview. A 5-item, open-ended questionnaire was used to capture providers' opinions of the patient portal. Providers included general practitioners (GPs), nurses, nurse practitioners (NPs), dieticians, diabetes educators (DECs), and other clinical staff. RESULTS: A total of 854 patients were consented for the questionnaire. Seventeen (8 male, 9 female) patients agreed to participate in a telephone interview. Sixty-four health care providers completed the five open-ended questions; however, an average of 48.2 responses were recorded per question. Four major themes were identified and will be discussed in this paper. These themes have been classified as: facilitators of disease management, barriers to portal use, patient-provider communication and relationship, and recommendations for portal improvements. CONCLUSIONS: This qualitative study shows that online chronic disease management portals increase patient access to information and engagement in their health care, but improvements in the portal itself may improve usability and reduce attrition. Furthermore, this study identifies a grey area that exists in the roles that GPs and AHPs should play in the facilitation of online disease management.

ß-blockade restores muscle sympathetic rhythmicity in human heart failure.

BACKGROUND: Muscle sympathetic nerve firing rate increases as chronic heart failure (CHF) progresses, yet its oscillation, particularly within the frequency range encompassing 0.13 Hz, diminishes. The current study tested the hypothesis that chronic therapy with lipophilic ß-adrenoceptor antagonists augments the modulation of muscle sympathetic nerve activity variability (MSNAV) at this frequency range. METHODS AND RESULTS: In 21 CHF angiotensin converting enzyme (ACE) inhibitor-treated patients (age: 53 ± 2, ejection fraction: 20 ± 2%), MSNA was recorded before and after 4 months of ß-blockade with either metoprolol (up to 50mg b.i.d.) or carvedilol (up to 25mg b.i.d.). Harmonic MSNAV was assessed by coarse graining spectral analysis. Both drugs lowered heart rate similarly (-13 ± 2 beats/min; P < 0.001) but neither affected MSNA burst frequency (-7 ± 4 bursts/min, not significant). Before ß-blockade, harmonic MSNA power in the region encompassing 0.13 Hz was essentially absent. Beta-blockade increased the mean values for total power (from 0.00 to 0.50 Hz; 5.2 ± 0.8 to 6.8 ± 1.2U(2); P < 0.001) and for harmonic MSNA spectral power across the 0.1-0.22 Hz frequency range (from 0.48 ± 0.10 to 1.50 ± 0.32 U(2), F = 12.2; P < 0.001). Both carvedilol and metoprolol had a similar effect. CONCLUSIONS: In patients with CHF receiving ACE inhibitors, adding a ß-adrenoceptor antagonist restores low and high frequency harmonic oscillations in MSNA. Beta-1 antagonism is sufficient to achieve this response. Augmented modulation of sympathetic outflow could contribute to the beneficial effects of ß-blockade in CHF on sudden death and disease progression.

Effect of angiotensin AT1 receptor blockade on sympathetic responses to handgrip in healthy men.

BACKGROUND: To determine whether angiotensin II (ANG II) contributes to the reflex skeletal muscle sympathoexcitation elicited by isometric and isotonic exercise, we tested the hypothesis that angiotensin AT(1) receptor blockade (ARB) would attenuate reflex sympathoneural responses to handgrip (HG) and to post-handgrip ischemia (PHGI). METHODS: Seventeen healthy men were studied before and 1 week after random double-blind crossover allocation to oral losartan (100 mg daily) and placebo. Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded at rest, and during 2 min bouts of isotonic HG at 50% maximum voluntary contraction (MVC) and isometric HG at 30% MVC, performed randomly, each followed by 2 min of PHGI. RESULTS: At rest, losartan doubled plasma renin (P = 0.01) and ANG II (P = 0.03) concentrations, and lowered BP (P < 0.01) yet had no effect on MSNA burst frequency or incidence. HR trended higher (P = 0.060). Losartan's hypotensive effect persisted throughout each exercise bout (P < 0.045). MSNA and HR responses to isotonic exercise and postexercise ischemia were not affected by losartan. Isometric exercise and postexercise ischemia increased MSNA on both sessions (all P < 0.01). Losartan augmented the HR response (P ≤ 0.03), and after losartan MSNA burst frequency (P < 0.01) and incidence (P < 0.04) were significantly higher at all time points, but the magnitude of the MSNA response to isometric exercise and postexercise ischemia was unchanged. CONCLUSION: In healthy men, short-term ARB does not attenuate reflex sympathoneural responses to HG or PHGI.

Dose-related effects of red wine and alcohol on heart rate variability.

In healthy subjects a standard drink of either red wine (RW) or ethanol (EtOH) has no effect on muscle sympathetic nerve activity or on heart rate (HR), whereas two drinks increase both. Using time- and frequency-domain indexes of HR variability (HRV), we now tested in 12 subjects (24-47 yr, 6 men) the hypotheses that 1) this HR increase reflects concurrent dose-related augmented sympathetic HR modulation and 2) RW with high-polyphenol content differs from EtOH in its acute HRV effects. RW, EtOH, and water were provided on 3 days, 2 wk apart according to a randomized, single-blind design. Eight-minute segments were analyzed. One alcoholic drink increased blood concentrations to 36 + or - 2 mg/dl (mean + or - SE), and 2 drinks to 72 + or - 4 (RW) and 80 + or - 2 mg/dl (EtOH). RW quadrupled plasma resveratrol (P < 0.001). HR fell after both water drinks. When compared with respective baselines, one alcoholic drink had no effect on HR or HRV, whereas two glasses of both increased HR (RW, +5.4 + or - 1.2; and EtOH, +5.7 + or - 1.2 min(-1); P < 0.001), decreased total HRV by 28-33% (P < 0.05) and high-frequency spectral power by 32-42% (vagal HR modulation), and increased low-frequency power by 28-34% and the ratio of low frequency to high frequency by 98-119% (sympathetic HR modulation) (all, P < or = 0.01). In summary, when compared with water, one standard drink lowered time- and frequency-domain markers of vagal HR modulation. When compared with respective baselines, two alcoholic drinks increased HR by diminished vagal and augmented sympathetic HR modulation. Thus alcohol exerts dose-dependent HRV responses, with RW and EtOH having a similar effect.

Behavioral neurocardiac training in hypertension: a randomized, controlled trial.

It is not established whether behavioral interventions add benefit to pharmacological therapy for hypertension. We hypothesized that behavioral neurocardiac training (BNT) with heart rate variability biofeedback would reduce blood pressure further by modifying vagal heart rate modulation during reactivity and recovery from standardized cognitive tasks ("mental stress"). This randomized, controlled trial enrolled 65 patients with uncomplicated hypertension to BNT or active control (autogenic relaxation), with six 1-hour sessions over 2 months with home practice. Outcomes were analyzed with linear mixed models that adjusted for antihypertensive drugs. BNT reduced daytime and 24-hour systolic blood pressures (-2.4+/-0.9 mm Hg, P=0.009, and -2.1+/-0.9 mm Hg, P=0.03, respectively) and pulse pressures (-1.7+/-0.6 mm Hg, P=0.004, and -1.4+/-0.6 mm Hg, P=0.02, respectively). No effect was observed for controls (P>0.10 for all indices). BNT also increased RR-high-frequency power (0.15 to 0.40 Hz; P=0.01) and RR interval (P<0.001) during cognitive tasks. Among controls, high-frequency power was unchanged (P=0.29), and RR interval decreased (P=0.03). Neither intervention altered spontaneous baroreflex sensitivity (P>0.10). In contrast to relaxation therapy, BNT with heart rate variability biofeedback modestly lowers ambulatory blood pressure during wakefulness, and it augments tonic vagal heart rate modulation. It is unknown whether efficacy of this treatment can be improved with biofeedback of baroreflex gain. BNT, alone or as an adjunct to drug therapy, may represent a promising new intervention for hypertension.

Nocturnal home hemodialysis improves baroreflex effectiveness index of end-stage renal disease patients.

BACKGROUND: In patients with end-stage renal disease receiving conventional hemodialysis, both the frequency with which brief rises or falls in systolic blood pressure initiate concordant changes in pulse interval (arterial baroreflex effectiveness index), and the gain of reflex heart rate responses to these stimuli (arterial baroreflex sensitivity) are diminished. In chronic renal failure, low baroreflex effectiveness index and baroreflex sensitivity are associated with increased rates of all-cause mortality and sudden death, respectively. Conversion to home nocturnal hemodialysis augments baroreflex sensitivity but its effects on baroreflex effectiveness index have not been reported. METHODS: In 20 consecutive hypertensive conventional hemodialysis patients training to transition to nocturnal hemodialysis (age 41 +/- 2 years; mean +/- standard error), baroreflex effectiveness index, baroreflex sensitivity (sequence method) and total arterial compliance (stroke volume/pulse pressure) were determined during quiet rest before and 2 months after conversion. RESULTS: With nocturnal hemodialysis, dialysis frequency doubled, the dose per session increased by 70% and antihypertensive medications were withdrawn (from 2.5 +/- 0.3 to 0.2 +/- 0.1 drugs/patient, P < 0.01) because systolic blood pressure fell (from 139 +/- 5 to 119 +/- 4 mmHg, P < 0.05). Baroreflex effectiveness index increased from (0.33 +/- 0.03 to 0.42 +/- 0.03, P = 0.01). Baroreflex sensitivity increased from 5.60 +/- 0.88 to 8.48 +/- 1.60 ms/mmHg (P < 0.05). Changes in total arterial compliance correlated with changes in baroreflex sensitivity (r = 0.63, P = 0.004) but not baroreflex effectiveness index (r = 0.05, P = 0.95), suggesting independent mechanisms for their attenuation and recovery in end-stage renal disease. CONCLUSION: Nocturnal hemodialysis increases baroreflex effectiveness index in addition to baroreflex sensitivity. The hypothesis that such changes might reduce cardiovascular event rates in this high-risk population merits prospective evaluation. More frequent engagement of the arterial baroreflex after conversion to nocturnal hemodialysis may improve short-term cardiovascular regulation.

Dose-related effects of red wine and alcohol on hemodynamics, sympathetic nerve activity, and arterial diameter.

The cardiovascular benefits of light to moderate red wine consumption often have been attributed to its polyphenol constituents. However, the acute dose-related hemodynamic, vasodilator, and sympathetic neural effects of ethanol and red wine have not been characterized and compared in the same individual. We sought to test the hypotheses that responses to one and two alcoholic drinks differ and that red wine with high polyphenol content elicits a greater effect than ethanol alone. Thirteen volunteers (24-47 yr; 7 men, 6 women) drank wine, ethanol, and water in a randomized, single-blind trial on three occasions 2 wk apart. One drink of wine and ethanol increased blood alcohol to 38 +/- 2 and 39 +/- 2 mg/dl, respectively, and two drinks to 72 +/- 4 and 83 +/- 3 mg/dl, respectively. Wine quadrupled plasma resveratrol (P < 0.001) and increased catechin (P < 0.03). No intervention affected blood pressure. One drink had no heart rate effect, but two drinks of wine increased heart rate by 5.7 +/- 1.6 beats/min; P < 0.001). Cardiac output fell 0.8 +/- 0.3 l/min after one drink of ethanol and wine (both P < 0.02) but increased after two drinks of ethanol (+0.8 +/- 0.3 l/min) and wine (+1.2 +/- 0.3 l/min) (P < 0.01). One alcoholic drink did not alter muscle sympathetic nerve activity (MSNA), while two drinks increased MSNA by 9-10 bursts/min (P < 0.001). Brachial artery diameter increased after both one and two alcoholic drinks (P < 0.001). No beverage augmented, and the second wine dose attenuated (P = 0.02), flow-mediated vasodilation. One drink of ethanol dilates the brachial artery without activating sympathetic outflow, whereas two drinks increase MSNA, heart rate, and cardiac output. These acute effects, which exhibit a narrow dose response, are not modified by red wine polyphenols.

A mobile phone based remote patient monitoring system for chronic disease management.

Rising concern over the poor state of chronic disease management led to the user-informed design and development of a home tele-monitoring system. Focus groups with patients and primary care providers guided the research team towards a design that would accommodate the workflow and concerns of the healthcare providers and the low use and comfort with technology found among the patient population. The system was trialed in a before-and-after pilot study of 34 patients with diabetes and hypertension. Findings demonstrate a significant improvement in systolic and diastolic blood pressure. An RCT beginning in 2007 is being conducted to confirm these findings. It is hypothesized that this user-centred approach, utilizing focus groups, iterative design and human factors methods of evaluation, will lead to the next-generation of home tele-monitoring applications that are more intuitive, less cumbersome, and ultimately bring about greater patient compliance and better physician management.

Endocardial and epicardial repolarization alternans in human cardiomyopathy: evidence for spatiotemporal heterogeneity and correlation with body surface T-wave alternans.

OBJECTIVES: The aim of this study was to define the spatiotemporal distribution of intracardiac alternans and its relationship to body surface alternans in humans. BACKGROUND: Spatial heterogeneity of alternans exists in the animal heart owing to nonuniform calcium cycling and restitution kinetics. Patients with cardiomyopathy manifest similar myocardial substrate, which might influence the distribution of intracardiac alternans and its projection onto the body surface. METHODS: Repolarization alternans was simultaneously measured from unipolar electrograms in the right ventricular endocardium, left ventricular (LV) epicardium, and the surface electrocardiogram in patients with cardiomyopathy (n = 14, LV ejection fraction 29 +/- 2%) during atrial pacing at cycle length (CL) 800, 600, and 500 ms. Alternans was determined from the entire JT interval as well as the early, mid, and late JT interval with spectral analysis. RESULTS: Alternans was not uniformly distributed within the heart, with alternating and nonalternating myocardial segments lying adjacent to one another. A greater number of epicardial sites exhibited alternans than endocardial sites at CL 600 ms. Temporal heterogeneity in alternans was present along the JT interval, and apical segments had proportionately less alternans in the late JT interval than mid or basal segments, resulting in apicobasal alternans heterogeneity in late JT interval. Discordant alternans was seen in 5 patients confined to the epicardium. Patients with surface alternans had a greater proportion of intracardiac sites with alternans when compared with those patients without surface alternans. CONCLUSIONS: Spatiotemporal heterogeneity and discordant alternans are evident in patients with cardiomyopathy. Greater spatial distribution of intracardiac alternans is associated with measurable body surface alternans.

Steeper restitution slopes across right ventricular endocardium in patients with cardiomyopathy at high risk of ventricular arrhythmias.

Steep action potential duration (APD) restitution slopes (>1) and spatial APD restitution heterogeneity provide the substrate for ventricular fibrillation in computational models and experimental studies. Their relationship to ventricular arrhythmia vulnerability in human cardiomyopathy has not been defined. Patients with cardiomyopathy [left ventricular (LV) ejection fraction <40%] and no history of ventricular arrhythmias underwent risk stratification with programmed electrical stimulation or T wave alternans (TWA). Low-risk patients (n = 10) had no inducible ventricular tachycardia (VT) or negative TWA, while high-risk patients (n = 8) had inducible VT or positive TWA. Activation recovery interval (ARI) restitution slopes were measured simultaneously from 10 right ventricular (RV) endocardial sites during an S1-S2 pacing protocol. ARI restitution slope heterogeneity was defined as the coefficient of variation of slopes. Mean ARI restitution slope was significantly steeper in the high-risk group compared with the low-risk group [1.16 (SD 0.31) vs. 0.59 (SD 0.19), P = 0.0002]. The proportion of endocardial recording sites with a slope >1 was significantly larger in the high-risk patients [47% (SD 35) vs. 13% (SD 21), P = 0.022]. Spatial heterogeneity of ARI restitution slopes was similar between the two groups [29% (SD 16) vs. 39% (SD 34), P = 0.48]. There was an inverse linear relationship between the ARI restitution slope and the minimum diastolic interval (P < 0.001). In cardiomyopathic patients at high risk of ventricular arrhythmias, ARI restitution slopes along the RV endocardium are steeper, but restitution slope heterogeneity is similar compared with those at low risk. Steeper ARI restitution slopes may increase the propensity for ventricular arrhythmias in patients with impaired left ventricular function.

Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study.

Increased repolarization heterogeneity can provide the substrate for reentrant ventricular arrhythmias in animal models of cardiomyopathy. We hypothesized that ventricular repolarization heterogeneity is also greater in patients with cardiomyopathy and ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans, VT/TWA) compared with a similar patient population without ventricular arrhythmia vulnerability (no VT/TWA). Endocardial and epicardial repolarization heterogeneity was measured in patients with (n = 12) and without (n = 10) VT/TWA by using transvenous 26-electrode catheters placed along the anteroseptal right ventricular endocardium and left ventricular epicardium. Local activation times (AT), activation-recovery intervals (ARI), and repolarization times (RT) were measured from unipolar electrograms. Endocardial RT dispersion along the apicobasal ventricle was greater (P < 0.005) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.005). AT dispersion was similar between the two groups. Epicardial RT dispersion along the apicobasal ventricle was greater (P < 0.05) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.05). AT dispersion was similar between the two groups. A plot of AT as a function of ARI revealed an inverse linear relationship for no VT/TWA such that progressively later activation was associated with progressively shorter ARI. The AT-ARI relationship was nonlinear in VT/TWA. In conclusion, patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA without associated conduction slowing. The steep repolarization gradients in VT/TWA may provide the substrate for functional conduction block and reentrant ventricular arrhythmias.

Vagal heart rate responses to chronic beta-blockade in human heart failure relate to cardiac norepinephrine spillover.

We have documented a pre-junctional beta-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic beta-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of beta-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55+/-2 [mean+/-S.E.]; ejection fraction: 20+/-2%), beta-blockade increased BRS from 4.8+/-0.9 to 7.9+/-1.3 ms/mm Hg (P<0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P<0.05). Chronic beta-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional beta-2 adrenoceptors that facilitate NE release.

Heart rate variability biofeedback as a behavioral neurocardiac intervention to enhance vagal heart rate control.

BACKGROUND: Patients with coronary heart disease (CHD) who experience depressed mood or psychological stress exhibit decreased vagal control of heart rate (HR), as assessed by spectral analysis of HR variability (HRV). Myocardial infarction and sudden cardiac death are independently associated with depression and stress, as well as impaired vagal HR control. This study examined whether a behavioral neurocardiac intervention to reduce stress or depression can augment cardiovagal modulation in CHD patients. We hypothesized that (1) cognitive-behavioral training with HRV biofeedback would augment vagal recovery from acute stress, and (2) vagal regulation of HR would be inversely associated with stress and depression after treatment. METHODS: This randomized controlled trial enrolled 46 CHD patients from 3 clinics of CHD risk reduction in Toronto and Vancouver, Canada. Subjects were randomized to five 1.5-hour sessions of HRV biofeedback or an active control condition. Outcome was assessed by absolute and normalized high-frequency spectral components (0.15-0.50 Hz) of HRV, and by the Perceived Stress Scale and Centre for Epidemiologic Studies in Depression scale. RESULTS: Both groups reduced symptoms on the Perceived Stress Scale (P = .001) and Centre for Epidemiologic Studies in Depression scale (P = .004). Hierarchical linear regression determined that improved psychological adjustment was significantly associated with the high-frequency index of vagal HR modulation only in the HRV biofeedback group. Adjusted R 2 was as follows: HRV biofeedback group, 0.86 for stress (P = .02) and 0.81 for depression (P = .03); versus the active control group, 0.04 (P = .57) and 0.13 (P = .95), respectively. CONCLUSION: A novel behavioral neurocardiac intervention, HRV biofeedback, can augment vagal HR regulation while facilitating psychological adjustment to CHD.